The inflammation induced by monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals is driven by interleukin (IL)-1β production. This later relies on NLRP3 inflammasome which can be activated by variation of ion concentration.To assess the role of osmolarity and water flux in MSU and CPP crystal-induced inflammation.In vitro, THP1 monocytes were stimulated by pyrogen-free synthetic MSU and CPP crystals in iso-, hypo- or hyperosmotic media. Cytokine production was quantified by ELISA in cell culture supernatants. Cell size was measured using video microscopy. The role of aquaporin channels was assessed by pharmacological inhibitor (mercury chloride, HgCl2). In vivo, murine air pouch model was used. MSU and CPP crystals were injected in air pouch of mice treated or not with HgCl2 or mannitol. Osmolarity of mouse sera and patient synovial fluids (SF) were measured using freezing point osmometer. The size of cells collected from SF was assessed with imageJ software.MSU and CPP crystal-induced IL-1β production was substantially reduced by HgCl2 treatment (MSU 4900 vs 880 pg/ml; CPP 10500 vs 980, p<0.0001) or when cells were cultured in hyperosmotic medium. MSU and CPP crystals induced a transient increase in cell size which was 1.6 and 1.5 bigger after 30 and 100 min of stimulation by MSU and CPP crystals, respectively. After 150 min of stimulation, cell size decreased to their baseline size. Cell size increase was abolished by HgCl2 or hyperosmotic medium. In vivo, MSU and CPP crystal-induced inflammation (assessed by cell infiltration, IL-1β and CXCL2 production in air pouch lavage) was drastically reduced by HgCl2 or mannitol treatment. The serum osmolarity was higher in mannitol-treated mice than untreated mice (320 vs 300 mmosm/L). In patients, cells collected from SF during CPP or MSU crystal-induced flares had a bigger size than cells collected from osteoarthitic SF. The osmolarity of MSU or CPP crystal-containing SF was lower than the osmolarity of osteoarthritic SF (270 vs 310 mmosm/L). Finally, the IL-1β concentration in SF was strongly correlated with cell size and SF osmolarity.These results suggest that the variation of osmolarity plays central role in MSU and CPP crystal-induced inflammation. Deciphering how crystals modulate osmolarity will identify new therapeutic targets.None declared